Over the past few years, a new generation of particularly potent broadly neutralizing antibodies (bNAbs) have been isolated from HIV-1-infected individuals. Passive transfer experiments showing that some of these antibodies are able to suppress virus replication below the limit of detection in animals have renewed interest in the development of antibody-based therapies to treat HIV-1 infection. Increasing evidence also suggests that Fc receptor (FcR)-dependent functions of antibodies, such as the elimination of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and the phagocytosis of antibody-opsonized immune complexes, are important for protection against immunodeficiency virus infection. These advances raise the possibility that immunotherapies designed to maximize FcR-mediated functions of antibodies may be developed to deplete viral reservoirs and contain HIV-1 replication in the absence of continuous antiretroviral therapy. Using variants of a bNAb with potent ADCC activity against HIV-1-infected cells, and infection of rhesus macaques with a pathogenic CCR5-tropic SHIV as an animal model, we will specifically address this hypothesis, as well as the fundamental antiviral mechanisms of antibodies mediated by FcRs important for suppressing immunodeficiency virus replication. In Aim 1, we will determine how species-specific differences and polymorphisms affect FcR recognition of antibodies in the rhesus macaque to provide the foundation necessary for investigating FcR-mediated antiviral activities of antibodies in this primate model. In Aim 2, we will compare variants of a bNAb with modifications to enhance FcR-dependent functions for their ability to clear virus-infected cells in animals. For these studies, will use viruses that are limited to a single cycle of infection to uncouple the FcR-mediated effects of antibodies on virus-infected cells from their effects on virus neutralization. In Aim 3, we will compare passively transferred antibodies with and without modifications to enhance FcR interactions for the ability to deplete viral reservoirs and delay viral rebound in SHIV-infected animals after withdrawal of antiretroviral therapy. In Aim 4, we will extend these studies to the use of AAV vectors for sustained antibody delivery to determine if enhanced FcR-mediated antiviral activity can durably suppress SHIV replication after discontinuing antiretroviral therapy. These unprecedented studies will advance our basic understanding of the capacity of non-neutralizing functions of antibodies to contain immunodeficiency virus infection and the therapeutic impact of enhancing FcR-mediated antiviral activity in a pre-clinical model of antibody treatment for HIV-1 infection.